The overall goals of this project are to determine whether there is a biological basis to the prevalence of inhalant abuse in adolescents and to better understand how inhalant exposure affects the developing brain. The Specific Aims are: 1) to establish one cause of inhalant abuse in adolescence using functional imaging and 2) to identify the structural and functional consequences of inhalant abuse on brain development. These studies are driven by the overarching hypothesis that the brain's response to inhalants is different in adolescents compared to adults. We believe that one cause of inhalant abuse is related to specific effects on the brain's mesolimbic reward system, primarily mediated by the neurochemical dopamine. We therefore expect that adolescents will have a greater dopaminergic response to inhalants than adults, which may increase their vulnerability to subsequent abuse. We believe the consequences of inhalant abuse are related to where inhalants go in the brain, and how long they reside in specific brain regions. We expect that brain regions where toluene accumulates will be selectively damaged, and that upon cessation from toluene, adolescents will recover function in these brain regions while adults will not. First, we apply functional imaging techniques that allow simultaneous measurement of brain function and behavior to identify the brain regions and neurochemical pathways associated with inhalant reward. Using Positron Emission Tomography (PET) and [11C]-raclopride, we will determine changes in dopamine release in response to an acute, rewarding dose of inhaled toluene. We expect that the magnitude of dopamine release differs in adolescents compared to adults, and that the degree to which inhalants stimulate dopamine will predict the likelihood of establishing a place preference. Next, we apply MRI to understand the ways that toluene abuse affects brain structure and PET with 2-deoxy-2-[18F]-fluoro-D-glucose (FDG) to understand how this relates to changes in brain function. Our preliminary data show severe deficits in brain metabolism associated with adolescent inhalant abuse that recovers following months of cessation from toluene. Here we extend these studies to explore how toluene changes brain structure in parallel with brain function and how this in turn, affects performance. Our preliminary data demonstrate that the proposed aims can be completed within the time frame proposed. By completing our proposed aims, we will address three fundamental questions. (1) Do inhalants activate brain reward systems to a different degree in adolescents compared to adults? (2) Can neurochemical imaging with [11C]-raclopride predict which individuals or age groups will find inhalants rewarding? (3), Is inhalant abuse more damaging to the developing brain than the mature brain? The pivotal biological role of the central nervous system (CNS) in healthy development and its susceptibility to toluene underline the urgent need for further clinical and experimental research in both adolescents and adults. The goal of these studies is to better understand inhalant abuse in adolescents. PUBLIC HEALTH RELEVANCE: The rapid development of brain imaging technologies and the continual emergence of new imaging paradigms hold great promise for revealing the causes and consequences of inhalant abuse, a significant public health problem that affected one in six children under the age of thirteen in 2007. Here we apply these technologies in an adolescent model of inhalant abuse to understand why children abuse inhalants more than adults, why products containing toluene are preferred, and how inhalant abuse affects the developing brain.